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Pharmaceuticals: Some General Aspects
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The three latest orphan medical products designated by the EMA early 2018 (EMA, 2018b) via accelerated assessment after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended marketing approval are Crysvita (burosumab), Prevymis (letermovir), and Jorveza (budesonide). The active substance of Crysvita (Kyowa Hakko Kirin Co. Ltd., Kyowa Kirin International PLC and Ultragenyx Pharmaceutical) is burosumab, a recombinant fully humanized monoclonal IgG1 antibody that binds to and inhibits the activity of fibroblast growth factor 23. The drug is indicated for the treatment of X-linked hypophosphataemia (XLH, a chronic progressive musculoskeletal disorder) with radiographic evidence of bone disease in children 1 year of age and older. The antiviral agent Prevymis (letermovir), a non-nucleosidic, inhibitor is used for prophylaxis of cytomegalovirus (CMV) infection and disease in adults and acts by inhibiting the human CMV viral terminase by a mechanism that remains to be elucidated (Ligat et al., 2018). CMV may cause life-threatening infections in immuno-compromised patients and serious congenital malformations. Prevymis is marketed by Merck & Co., Inc. (or Merck Sharp & Dohme (kurz MSD)) and was developed by AiCuris up to the clinical phase 2b. AiCuris received from Merck €30 million in addition to €105 million that became due after approval of Prevymis by the FDA in November 2017. Jorveza (with the glucocorticosteroid budesonide), marketed by Dr. Falk Pharma GmbH, Germany, is a medicine used to treat adults with the rare inflammatory disease eosinophilic esophagitis, a designation stemming from the fact that in the tissue of the esophagus in patients with this disease numbers of white blood cells called eosinophils are very high. Budesonide acts by preventing antigen-stimulated secretion of proinflammatory signal molecules such as thymic stromal lymphopoeitin (TSLP, a protein belonging to the cytokine family and produced mainly by non-hematopoietic cells (its expression is linked not only to eosinophilic esophagitis but also to other diseases, e.g., asthma, inflammatory arthritis, atopic dermatitis, etc.), interleukin-13 (the IL-13 protein is associated primarily with the induction of airway diseases), and eotaxin-3 (or chemokine (C-C motif) ligand 26 (CCL26) in the esophageal epithelium. Eotaxin-3 is a small cytokine belonging to the CC chemokine family and chemotactic for eosinophils (and basophils); for the regulatory role of this human chemokine in connection with attracting eosinophils and basophils, see Petkovic et al. (2004).
Topical application of celastrol alleviates atopic dermatitis symptoms mediated through the regulation of thymic stromal lymphopoietin and group 2 innate lymphoid cells
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Jae Kwon Lee, Jin Kyung Seok, Ilyoung Cho, Gabsik Yang, Kyu-Bong Kim, Seung Jun Kwack, Han Chang Kang, Yong-Yeon Cho, Hye Suk Lee, Joo Young Lee
Thymic stromal lymphopoietin (TSLP) is expressed by dermal epithelial cells that stimulate Th2 differentiation to initiate Th2 immune responses (He et al. 2008). The expression of TSLP is involved in the pathogenesis of various diseases including atopic dermatitis, asthma, and inflammatory arthritis (Ebner et al. 2007; Yang et al. 2018; Ying et al. 2005). TSLP expression levels are up-regulated in atopic dermatitis patients skin lesions (Soumelis et al. 2002). In atopic dermatitis, TSLP is produced by skin keratinocytes in response to external stimuli such as allergens, cytokines, viruses, bacteria and fungi, and plays an important role in early development of diseases (Ziegler 2012). Increased TSLP levels stimulate immature dendritic cells to express OX40 ligand in an antigen-specific manner (Gilliet et al. 2003). The expression of OX40 ligand-dendritic cells promotes the differentiation of naïve CD4 T cells into Th2 cells (Ohshima et al. 1997). TSLP also directly stimulates development of naïve CD4 T cells or CD8 T cells into Th2 cells. The activation of TSLP receptor (TSLPR) initiates IL-4 gene transcription, which induces positive feedback to upregulate the TSLPR located on CD4 T cells (Omori and Ziegler 2007). It is noteworthy that Th2 cells produce increased Th2 cytokines levels of IL-4, IL-5, and IL-13 (Leyva-Castillo et al. 2013). Th2 cytokines lead to elevated IgE production by inducing class switching in B cells, and skin inflammatory responses, exacerbating skin barrier defects in atopic dermatitis (Guttman-Yassky and Krueger 2017). Therefore, TSLP expression is considered a hallmark of early pathogenesis of atopic dermatitis (Wang et al. 2013).
Genetic variants affecting chemical mediated skin immunotoxicity
Published in Journal of Toxicology and Environmental Health, Part B, 2022
Isisdoris Rodrigues de Souza, Patrícia Savio de Araujo-Souza, Daniela Morais Leme
TSLP is a secretory cytokine of thymic stromal cells that uses the combination of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2) to activate signal transducer and activator of transcription 5 (STAT5) (Rochman et al. 2010). STAT5 induces genes that regulate cell proliferation, differentiation, survival, and inflammation (Ando et al. 2014; Hennighausen and Robinson 2008). TSLP is produced by keratinocytes, fibroblasts, epithelial cells, basophils, and stromal cells (Lee et al. 2021; Rochman et al. 2010) and binds to TSLP receptor (TSLPR) (Quentmeier et al. 2001). TSLP receptor is present on DCs, T and B lymphocytes, NK cells, ILC2, eosinophils, basophils, and monocytes (Halim et al. 2012; Kim et al. 2013; Ziegler and Artis 2010).